1, 2, 5-thiadiazole-3, 4-dicarboxamide



Un fiid SW Patent *i 1,990,408 Z .1,2,53HIADIAZOLE 3A-DICARBOXAMIDE Marvin Carmack, 1127 1st St., 'Bloomington, Ind., Daniel Shew, Clifton, NJ. (184 Newman St., Metuchen, NJ.), and Leonard M. Weinstock, Clifton, NJ.

(300D Crowells Road, Highland Park, NJ.)

No Drawing. .Origin'al application July 23, 1958, Ser.

No. 750,419. Divided and this application Mar. 3, 1960, Ser. No. 15,020 v I I 2 Claims. (Cl. 260-302) years. However, prior this invention, 3,4-disubstituted 1,2,5-thiadiazoles were completely unknown. It is an object of this invention to provide for the first time 1,2,5- thiadiazoles substituted at the 3 and 4 positions of the heterocyclic ring. It. is a further object to provide a syn; thesis of such compounds-from 4-nitro-2,l,3-benzothiadiazole. A still further object is the provision .of 1,2,5.- thiadiazole-3,4-dicarboxylic acid by oxidation of 4-nit ro- 2,1,3-benzothiadiazole.. Anadditional object is .the' pro vision of mono and disalts of l,2,5-thiadiazole-3,4-dicarboxylic acid, and of the hydrocarbon esters of said acid. X

Still another object is the provision of the amides and acid halides derived the aforementioned dicarboxylic acid. It is yet another object to make available syntheses of such 1,2,5-thiadiazole-3,4-dicarboxylic acid a, .new compound having the following structural formula:

5 coon N coon This compound is strongly acidic and very soluble in water and polar organicsolvents. When pure it existsa-s a'high melting crystalline solid.

It has been discovered that.1,2,5-thiadiazole-3,'4-dicarboxylic acid may be prepared by oxidation ofA-n'itro- 2,1,3-benzothiadiazole with permanganate under the conditions described below'. This process may be pictured structurallyasfollows: F

metal permanganate results in oxidation of the benzothia- 'diazole to 1,2,5-thiadiazole.-3,4-dicarboxylic acid.

.It is preferred to employ potassium permanganate as thezoxidizing agent although other permanganates-such as the sodium or barium compounds may be utilized.- The oxidationis normally carried out in an aqueous reaction medium at temperatures between about 40 C. and 75 C; and preferably-in the range of 50-70 C. 'For best results from6-8 moles of permanganate are employed for every mole of 4-nitro-2,l,3-benzothiadiazole. "Six moles arere- 7. quired by the stoichiometry of .the reaction-and onlya. 'tlculafly the alkyl esters- 45 ylic acid precipitates from solution in a highly pure form.

Patented June 27, 1961 3 excess over thistheoretical amount has been necessary to obtain satisfactory results. Larger quantities of oxidizing agent may, of course, be employed if desired.

For convenienceinconducting the reaction it is preferred to [add the permanganate salt to a solution of 4-nitro-2,1,3-benzothiadiazole gradually over a period of one-half to two hours, either in solution or as a solid. The oxidation proceeds rapidly and is ordinarily substan tially complete as soon as the addition of oxidizing agent is finished. As will be recognized by those skilled in art, completion of the reaction may be readily determined by the persistence in the reaction mixture of the characteristic blue-purple permanganate color.

The pH of the reaction medium is important to the successful oxidation of 4-nitro-2,1,3-benzothiadiazole to 1,2,5 -thiadiazole-3,4-dicarboxylic acid. For best results,

' the initial pH of the benzothiadiazole solution should be about 6-7. As the oxidation proceeds the pH will gradually become alkaline until the final pH is about 10. As long as the pH is about neutral or alkaline the desired product is obtained. An acidic permanganate oxidation, however, should be avoided in the process, i.e. during the oxidation the reaction mixture should not become strongly acidic. T

I It be realized that 1,2,5-thiadiazole-3,4-dicarboxylic acid is formed in the reaction mixture as a salt, the particular salt depending upon the permanganate salt used as the oxidant. Thus, when potassium permanganate is uti-' lized-as the oxidizing agent, the dipotassium salt of 1,2,5 thiadiazole-3,4-dicarboxylic acid is formed in the neutral I or' alkaline oxidation medium; correspondingly, the so dium salt of the diacid is produced when sodium permanganate is the oxidizing agent. The free acid and/or other salts may be prepared therefrom as discussed below.

l,2,5-thiadiazole-3,4-dicarboxylic acid and its alkali metal salts are highly water-soluble substances. 7 For this reason we prefer to purify and isolate the acid by way of a waterfinsoluble heavy metal salt, preferably the mono-silver salt. For example, the aqueous solution obtained upon oxidation of 4-nitro-2,1,3-benz0thiadiazole may be filtered to remove insolubles and the resulting filtrate, which contains a water soluble alkali metal salt of l,2,5-thiadiazole-3,4-dicarboxylic acid, made strongly acidic with nitric acid. A water soluble silver salt'such assilver nitrate is then added whereupon the highly insoluble mono-silver salt of 1,2,5-thiadiazole-3,4-dicarbox- This latter salt may then be converted to substantially pure free acid by removal of the silver therefrom with an acid such as hydrochloric, hydrobromic, hydriodic acids or hydrogen sulfid'e' According to an additional embodiment of this invention, mono anddisalts of 1,2,S-thiadiazole-3,4-di- .carboxylic acid may be prepared by treating the free acid with a base. In this manner, the ammonium salts, alkali metal salts such as sodium and potassium derivatives, alkaline earth metal salts such as the barium and calcium salts, or heavy metal salts may be obtained. In order to prepare a di-salt an aqueous solution of the free acid is treated with excess base. The mono salts are convenientlyprepared by treating an aqueous solution of -1,2,5-thiadiazole-3,4-dicarboxylic acid with a base-t0 a pH of about 3. In synthesizing these salts, we prefer to utilize bases such as ammonium hydroxide, potassium hydroxide, sodium hydroxide and the like. The salts are conveniently isolated by precipitation from the aqueous obtained by reaction of'analkali metal or ammonium salt of l;25 thiadiazole 3;4 dicarboxy1ic acid' with'analkanol in the presence of a strong acid. It is desirable to carry 7 out the esteriiication process in the cold, i.e. attemperaeraser about; to 15 f Cfalthfou'g'h higher"'rea'cit ion" ternrsa' qeensed if desired. irm rower ana mic estei's''such. 5ST 34 dicarb6meth6iy l ,2,5'-thiadiazolej; V 53.4- dic'arlietlioiiy-l2;5-thiadia2ole; '-aamnnewfepex -rasmi aiazeie and mniearbebutexy 1,2;sahi5dia2b1e are obtained by suspending an ammonium or alkali metal saltof'thelree acidin theapiirofiriate iewer' 'alkariolsaturatedfwith 7 dr'fhydrogenbhIoriEle. "The" reacrien" mixture is held in tlie Cold for" from 205Ufi5i1rs in or'drtd obfain ni lir ilii'ntestrification. Tlie'se 15wer alKylesterS', are"hi,gh boilifig oils mamas reevered' "item; the reaction'iniiitui' by methods known to'oneslc'illd irf'this art. .Weprefer to emfiloy-thefmono ari'rnionium salt of 1 ;Z,5;thiadiaaole 34fdiearboitylic acidas starting material for; the synthesis; of the esters because thatis'alt is highly crystalline and readily-purifi ed. However, other .s alts $9 111 as the mono-potassinm the mono-sodiurnfthe diamrncfnium and di-potassium salts could also be utilized fenth e W asse- ,7 r gtlternatively. the estersxrnay be synthesized in hi gh yield trorn .l,2,5;thiadiazole-3.,fl-dicarboxylic acid itself byt pat e ee d a i w th a oh and the i he presence of a strong acid.

mono esters of -l,2,5 thiadiagole-3, t-dicarboxylic acid may bejr epared by treating the-n1ono-silver saltyvith an;;al kyl -iodide, such as methyl orf'e'thyl iodide,-;i n -an .ora ie lvent- B zenei l e e hem Pa l r y suitable solvents for; this;purj ose. In; this-fashionthere may be obtained esterssuch as the nrono-methyL- monoethyl, :gnbiro-prbpyl and-mono-butyl esters of l- ,2 ,5-thiadi o e-i tr c bexy .ac r s V In; accordance with a still turtherembodiment 0E this invention there are provided the amide and acid halide derivatives of 1.2.5 thiadiazole 3.4 dicarboxylic-iaeid. The amides are synthesizedby-treatingan estenrand preferably a loweralkyl ester, of the free acimwit-heammonia. For "example. j3v-c'arboxamido l-,2-,5thiadiazole- .4-carbvoxylic acidais obtained byqreaction of amonolower alkyl ester of l.2,i1thiadiazole-3,4-dicarboxylic iacidwith aqueous -arnmonia. .T'Ihe. 3,4-diamide is rproducedvon treatment oflower allgyl '1;2;5-thiadiazole-3;4 dicarboxylate 'anhydrousramrnoniain the cold;

. Alternatively.the-diamide' maybe prepared fromz the was heated to 60 C. on a steam bath and a solution of 1-31-gramsof potassium permanganate (:0.-828"mole) in the additio'n'ap' o'cl wasifdestrdyed'byithezadditiontof a small amqun of hanel. The mangenese nioxi le' was' separated friom 'the hwsolution by filtratiomand washed tibnofsilver siilfide was" complete. The resulting suscontacting said; material with ammonia. 'lfhe-aacidihalides are produced on treatment of analkali metal-salt of 1.25- :thiadiazole-S,4-dicarboxylic "acid; such as 'the potassium salt, with ahalogena'ting agent. Halogenating'agentssuch as thionyl chloride or thionylrbromide ares-particularly "andparticularlyl.2,5rthiadiaz0le-3,4-dicarboxamide,.havc

significant anti diabet-ic activity and may be-"emp1oyed*as anti-diabetic agents.

The 1,2,5 thiadiazole 3',4 dicarboxyliv acid= and=1the 7 several salts, esters; amides acid halides and like"'deriva-' tives described herein may-be converted -one'-to: another :asdescribed'in more detail in the detailed examples which follow, such inter-conversions and"reactions; and thefirew gcompounds produced'thereby area partof the instant in- .vention.

EXAMPLE 1 1,2,5 rhiadmzoesaawziwarflm and i r n bf #nitro-Z.1 ,3 benzotbiadiazole adios .mole) wasfslun iedzin" -500%":n1.-.of- -water.

pension w snre atd' with 5 rams is; activated charcoal and filteredmy 'gravityfthe precipitated silver sulfide was washed with lOOfinl: or water. The combined filtrates"and"-'waslfes were"evaj;iorate d' to'a moist residue and thei-'l asttraces-of water wereremoved i'bydrying overphcrsphemsf entoxide for few hours. The1;2,5-

2*:1'0. ma af0}21045332108.

J EXAMPLE 2 Salts of 1,2,5-thiadiazble 3j4-dicarboxylic acid A. Mono-silver salt.Additionof a silver nitrate so lution to an aqueous solution-"of 1,2,5-thiadiazole-3,4-dicarboxylic.acid precipitated the mono-silver salt of the acid. product 'Wasf"purified' 'by recrystallization from libt water. "It doesno'f'rnelt, bntfblaclrens graduallyfbetween 235-255 C. i

'BfMiihp fimmoiiiumfis'alt finimoniuni hydroxidewas ed '10 aqueous solntion of 1,2;5-thiadiazole=3,4;nicarboxylicacidto a'pHbf'Bi Oncoolingffsomebf the salt'erystallizesafidthe remainderis recipitated bythe addition of acetone to the filtrate. "Onfiecrystall'i'zfation from water-acetone the mono-ammonium salt is obtained, melting point-253-2-54" C.

Analysis.Calculat ed for CJ-I N 0 S:*"C,-25.13; H, 2.64; N, 21.99; S, 16.77. Fonnd:-: C. 25.65; H, 2.67; N, 21.89; 8, 16.53. d I

C. Diammonium- 'salL-An excess of ammonium hydroxide was added to an aqueous solution of 1,2,5-thiadiazole-3g4t-dicarboxylic acidiand san:: eqnalwoluinezbflacetonei-addedito the ammoniaai solution. Y'The IecipitMe'd diammofiium: salt was: collected byzfiltration vand dried.

.rcarbexylidmid to atbH eof -Seandeanerqdahpbrtionzof acetone wasitliemadded. fl hezmono potassiumesaltacrysi-talliz'emeandasaltwaszpurifiedeby feerystaflizatiomfmm 'r-wateraeetonei anelti-ng pbintfiQSiLC.', 4

Analysis-Calculated for C HN SO K: C, 22.64; H, 0.48; N, 13.20. Found: C, 22.47; H, 0.31; N, 13.21

E. Dipotasrium MIL-The dipotassium salt was prepared and purified in the same manner as 'the 'diammonium salt using potassium hydroxide in 'place' of ammonium hydroxide. Melting point 310 C. I

These salts are useful in purifying the free acid, and as intermediates in the synthesis of esters and acid halides of 1,2,5-thiadiazole-3,4-dicarboxylic acid."

, EXAMPLE 3 1,2,5-thiadiazole-3,4-dicarbxylic acid di-acid chloride One gram of mono-potassium-1,2,5-thiadiazole-3,4- dicarboxylate was added to ml. of thionyl chloride. The mixture was boiled under reflux for one hour and the excess solvent was then removed in vacuo. The resulting residue was sublimed at reduced pressure (50 3 mm.) and 475 mg. of the white crystalline 1,2,5-thiadiazole-3,4-dicarboxylic acid di-acid chloride was obtained. The melting point was 47 C.

Analysis.Calculated for C Cl N SO Cl, 33.60; S, 15.19. Found: Cl, 33.52; S, 14.70.

On treatment with ammonia in the cold, this material is converted to 3,4-dicarboxamido-1,2,5-thiadiazole.

EXAMPLE 4 4-carbomethoxy-l ,2,5thiadiaz0lc-3-carb0xylic acid Two grams of recrystallized mono-silver-1,2,5-thiadi azole-3,4-dicarboxylate was mixed with 20 ml. of dry benzene and 2.3 grams of distilled methyl iodide, and the resulting mixture stirred for 36 hours. The yellow precipitate of silver iodide was removed by filtration and washed well with ether. The combined filtrate and washes were evaporated under reduced pressure, leaving 4-carbomethoxy-1,2,5-thiadiazole-3-carboxylic acid as a clear light yellow oil which slowly crystallized on standing at 0 C. The solid melted at 7478 C. Sublimation of this material at 60/ 0.1 mm. and then recrystallization of the sublimate from a mixture of ether and petroleum ether raised the melting point of 8081 C.

Analysis.Calcd. for C H N SO C, 31.91; H, 2.14; N, 14.89; S, 17.04. "Found: C, 31.70; H, 2.12; N, 14.91; S, 16.77.

EXAMPLE 5 4-carb0meth0xy-1,2,5--1'hiadiazole-3-carboxylic acid A suspension of 8 grams of the mono-silver salt of 1,2,5-thiadiazole-3,4-dicarboxylic acid in a solution of 6 ml. of methyl iodide in 80 ml. of dry ethyl ether was stirred at room temperature in the dark for 43 hours. The resulting solid was removed by filtration and treated with a fresh solution of 5 ml. of methyl iodide in ethyl ether for 76 hours. The yellow precipitate of silver iodide was removed by filtration, and the ether solutions combined. Removal of the ether by distillation in vacuo gave 5 grams of 4-carbomethoxy-1,2,5-thiadiazole-ca.rboxylic acid as a pale yellow viscous oil which slowly solidified on standing.

EXAMPLE 6 4-carboxamido-l ,2,5-rhiadiazo'le-3-carb0xylic acid 1.27 grams of 4-carbomethoxy-1,2,5-thiadiazole-3-car boxylic acid was shaken vigorously with a solution of 2 ml. of concentrated ammonium hydroxide in 5 ml. of water. A light brown solid separated which was removed by filtration. This was crude 1,2,5-thiadiazole-3,4-dicarboxamide. The filtrate was acidified with nitric acid, and the light tan solid which formed was collected by filtration. Recrystallization of this material from 50 ml. of acetone gave 4-carboxamide-1,2,5-thiadiazole-3-carboxylic acid as short colorless prisms, melting point 219- 220.5 C.

Analysis.Calculated for C H N O S: C, 27.75; H, 1.75; N, 24.28; S, 18.53. Found: C, 27.88; H, 2.00; N, 24.15; S, 18.32.

v EXAMPLE 7 I .{Qqdkbome'thoxyJ,2,5-thiadiazole-3-carbonyl chloride i 3.1 grams of 4-carbomethoxy-1,2,5-thiadiazole 3-car boxylic acid was refluxed with 5 ml. of thionyl chloride in 10 ml. of. benzene fortwo hours. At the end of the reflux period, the reaction mixture was cooled, and the benzene and thionyl chloride removed by evaporation in vacuo. The amber liquid residue was distilled, and 4-carbomethoxy-1,2,5-thiadiazole-3-carbonyl chloride obtained as a pale yellow oil boiling point 8892 C./ 0.5 mm.

Analysis.Calculated for C H N O SCI: C, 29.08; H, 1.46; N, 13.56; C], 17.17. Found: C, 30.18; H, 1.34; N, 13.51;Cl, 15.71.

EXAMPLE 8 3,4-dicarbomethoxy-l,2,5-thiadiaz0le I An ice-cooled suspension of 2.12 grams of 1,2,5 thiadiazole-3,4-dicarboxylic acid mono-ammonium salt in 25 ml. of dry methanol was saturated with hydrogen chloride gas. The reaction mixture was allowed to stand in the refrigerator for 40 hours, filtered, and the colorless inorganic precipitate washed with methanol. The filtrate was concentrated until the formation of two liquid phases. One phase was removed by extraction of the concentrate with three por-tionsof ether (totaling ml. Evaporation of the ether extracts yielded a yellow oil which was distilled at 129/4 mm. pressure to give 3,4-dicarbomethoxy-1,2,5-thiadiazole as a white viscous liquid which solidified in the cold. A max. 263-264 log e=4.00, A min. 233 log e=3.13.

EXAMPLE 9 3 ,4-dicarbomethoxy-1 ,2,5-thiadiaz0'le 3.9 grams of the mono-ammonium salt of 1,2,5-thiadiaole-3,4-dicarboxylic acid was suspended in 45 of methanol. The mixture was cooled in ice and saturated with dry hydorgen chloride. It was then held at about 0-5 C. for 46 hours at the end of which time the hydrogen chloride was neutralized by the addition of solid sodium bicarbonate. The resulting white precipitate was removed by filtration and Washed with methanol. The combined filtrate and washes were evaporated under vacuum to a yellow oil. Ethyl ether was added to dis solve the oil, and the mixture was decanted from a small water layer. The ether was removed in vacuo, and the oil was distilled at 0.2 mm. Three fractions were obtained over a range of 89-97 C., totaling 3.44 grams. These were allowed to solidify partially at room temperature. Pure. 3,4-dicarbomethoxy-1,2,5-thiadiazole was prepared by combining the solid portions of the three fractions and redistilling at 0.1 mm. The product was a colorless viscous liquid, boiling point 84-85 C./0.1 mm.

Analysis.Calcd. for C H N O S: C, 35.64; H, 2.99; N, 13.85; S, 15.88. Found: C, 36.01; H, 3.03; S, 15.77.

EXAMPLE 10 1,2,5-thiadiazole-3,4-dicarboxamide Anhydrous ammonia gas was passed through a solution of 0.75 gram of 3,4-dicarbomethoxy-1,2,5-thiadiazole in 10 ml. of methanol until the solution was saturated. The reaction mixture was then allowed to cool in the cold for several hours. The colorless crystals which deposited were filtered and washed several times with methanol. Recrystallization of the crystals from hot water yielded substantially pure 1,2,5-thiadiazole-3,4-dicarboxamide, melting point 240 C.

Analysis.-Calod. for C H N O- S: C, 27.90; H, 2.34; N, 32.54; S, 18.63. Found: C, 27.95; H, 2.34; N, 32.40; S, 17.52.

EXAMPLE 11 l ,2 ,5 -thiadiazole-3,4-dicarb0xamide 0.504 gram of 4-carbomethoxy-1,2,5-thiadiazole-3-carhonyl chloride was added dropwise to 5 ml. of ice-cold 3,4-dicarboxamide separated as a .white, finely crystalline.

It was recovered by' filtration; washed with' methanol and .EXAMBLE 12 V 3g4 dicarbomethoxy-1,2i5-thiadiazole -.0ne gram of 1,2,5-tl1iadiazole-3,4-dicarboxylio .acid was added to ml. of methanol. The resulting mixture was .cooled and .then saturated -with dry hydrogen: chloride gas, ;;'I'hemixturewaswmaintainedat 0-10 C. for about hours aridthen the excess acid neutralized with sodium bicarbonate. :The'" resulting 1 precipitate was re- ;moved byifiltering' and 'thei'filtrate" concentrated to an oil in vacuo. The oily dimethyl ester of =1; 2,5-thiadiazole- 3,4-dicarboxylic acidlwas extracted in a small volume of ethyl ether. andthev ether was then removed by concentration and the oil idistillecl at a pressure of 0.2 mm. The-material boiling-in the temperature range of '90'-97 C. .WascbIIected and further "redistilled' as described'in 'Example"9-to give substantially 'pure 3g4-dicarbometh OxY-EZZS-thiadiazole. 7 1 "When this process is carriedout'employingethanol'as the solvent in place of methanol, there is obtained 3",4- dicarboethoxy-1;2,5 thiadiazole.

These esters, and'other'lower'alkyh esters which are prepared from the 'free acid-in the *same'manner, are usefulintenmedriates in thesyn'thes-is of the diamicle-as 'sefforthiin Example 10.

v p 7 :EXAMPLE 13 W 3,4-dicyanp-L2;5-thiadiazole I If-Aasolution (10.96 gram of-3',4dicarboiramido-12,5- thiadiazcle in. 6 .ml. .of phosphorus. .oxy'ehloride lwas. refluxed for about 40 minutes. "The mixture Lwas-then chilled andpoured onto 250 ml. of-crushed ice. Themix- .ture .lwass'tirrednntil the ice had melted and -then -.extraoted'with three. ml. portions ofe'ther. The.-ether extracts were combined, Washed with 20 m1. of sodium carbonate solution, washed with water and then dried over sodium sulfate. The ether was removedain vacuo leaving acrystalline residue of 3,4-dicyano-1,2,5-thiadi- 'azole;meltingpoint'47 49 C.

"Thismaterial is activeagainst'free-living nematodes such'as Penagrllus rdivivus and'against soil' fungi such as-Fusarium.

-Any departure from the above description which conforms to'the present invention is intended to be included within the scope ofthe claims.

Whatis claimed is: A 1. 1',2,5-thiadiazole-3Adicarboxamide. 2. The process which comprises treating a 3;4-dicarbolowenalkoxy:1,2,5-thiadiazole "with anhydrousammonia thereby producing 3,4=dicarboxamido-1,2;5-thiadiazole.

No references cited.

"new ti 

1. 1,2,5-THIADIAZOLE-3,4-DICARBOXAMIDE. 